Transcript

Each tablet contains 10 mg of nicorandil.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM

Tablet.
Off-white, round, with faceted edges, scored on one side and bearing the inscription IK10.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications

Ikorel is indicated in adults for the symptomatic treatment of patients with stable angina
pectoris who are inadequately controlled or have a contraindication or intolerance to first-line
antianginal therapies (such as beta-blockers and/or calcium antagonists).

4.2

Posology and method of administration

Posology
The usual therapeutic range is 10 to 20 mg twice daily. The usual starting dose is 10 mg
twice daily (bid), in the morning and in the evening preferably. It is recommended that the
dose be titrated upwards in accordance with the patient’s needs, response and tolerance up to
40 mg twice daily, if necessary. A lower starting dose of 5 mg twice daily may be used in
patients particularly prone to headache.
Elderly
There are no special dose requirements for elderly patients, but as with all medicines, use of
the lowest effective dose is recommended.

Patients with liver and/or renal impairment
There are no special dosage requirements for patients with liver and/or renal impairment.
Paediatric population
Ikorel is not recommended in paediatric patients since its safety and efficacy have not been
established in this patient group.
Method of administration
Ikorel is administered by oral route.
The tablets are to be swallowed in the morning and in the evening as a whole with some
liquid.
Administration is independent of food intake.

4.3

Contraindications

• Hypersensitivity to nicorandil or to any of the excipients listed in section 6.1.
• Patients with shock (including cardiogenic shock), severe hypotension, or left ventricular
dysfunction with low filling pressure or cardiac decompensation.
• Use of phosphodiesterase 5 inhibitors, since this can lead to a serious drop in blood
pressure (see section 4.5).
• Use of soluble guanylate cyclase stimulator(s) (such as riociguat) since it can lead to a
serious fall in blood pressure (see section 4.5).
• Hypovolaemia.
• Acute pulmonary oedema.

4.4

Special warnings and precautions for use

Ulcerations
Gastrointestinal ulcerations, skin and mucosal ulceration have been reported with nicorandil
(see section 4.8).
− Gastrointestinal ulcerations
Nicorandil induced ulceration may occur at different locations in the same patient. They
are refractory to treatment and most only respond to withdrawal of nicorandil treatment.
If ulceration(s) develop, nicorandil should be discontinued (see section 4.8). Healthcare
professionals should be aware of the importance of a timely diagnosis of nicorandilinduced ulcerations and of rapid withdrawal of nicorandil treatment in case of occurrence
of such ulcerations. Based on available information, the time between starting nicorandil
use and the onset of ulceration ranges from shortly after initiating nicorandil treatment to
several years after starting nicorandil.
Gastrointestinal haemorrhage secondary to gastrointestinal ulceration has been reported
with nicorandil. Patients taking acetylsalicylic acid or NSAIDs (non-steroidal antiinflammatory drugs) concomitantly are at increased risk for severe complications such as
gastrointestinal haemorrhage. Therefore caution is advised when concomitant use of
acetylsalicylic acid or NSAIDs and nicorandil is considered (see section 4.5).

If advanced, ulcers may develop into perforation, fistula, or abscess formation. Patients
with diverticular disease may be at particular risk of fistula formation or bowel perforation
during nicorandil treatment.
Gastrointestinal perforations in context of concomitant use of nicorandil and
corticosteroids have been reported. Therefore, caution is advised when concomitant use is
considered.
− Eye ulcerations
Very rare conjunctivitis, conjunctival ulcer and corneal ulcer have been reported with
nicorandil. Patients should be advised of the signs and symptoms and monitored closely
for corneal ulcerations. If ulceration(s) develops, nicorandil should be discontinued (see
section 4.8).
Decrease of blood pressure
Caution is advised if nicorandil is used in combination with other medicinal products with
blood pressure lowering effect (see sections 4.5 and 4.8).
Heart failure
Due to lack of data, caution is advised to use nicorandil in patients with heart failure class
NHYA III or IV.
Hyperkalaemia
Severe hyperkalaemia has been reported very rarely with nicorandil. Nicorandil should be
used with care in combination with other medical products that may increase potassium levels
(see sections 4.5 and 4.8).
Desiccant
The tablets are sensitive to moisture; hence the patients should be advised to keep the tablets
in their blister until intake. Besides the nicorandil tablets, each blister contains active
substance-free silica gel tablets as desiccant in a separate blister segment which is marked
accordingly. The patients should be advised not to take these tablets. Although any accidental
intake of this desiccant is usually harmless, it may alter the scheduled intake of the active
tablets.
Paediatric population
Ikorel is not recommended in paediatric patients since its safety and efficacy have not been
established in this patient group.
G6PD deficiency
Ikorel should be used with caution in patients with glucose-6-phosphate dehydrogenase
deficiency. Nicorandil acts in part through its organic nitrate moiety. The metabolism of
organic nitrates can result in the formation of nitrites which may trigger methemoglobinaemia
in patients with glucse-6-phosphate dehydrogenase deficiency.

4.5

Interaction with other medicinal products and other forms of interaction

Concurrent use of nicorandil and phosphodiesterase 5 inhibitors, e.g. sildenafil, tadalfil,
vardenafil, is contraindicated, since it can lead to a serious drop in blood pressure (synergic
effect).
Concomitant use of soluble guanylate cyclase stimulators (such as riociguat) is
contraindicated, since it can lead to a serious drop in blood pressure.

Therapeutic doses of nicorandil may lower the blood pressure of hypotensive patients.
If nicorandil is used concomitantly with antihypertensive agents or other medicinal products
with blood pressure lowering effect (e.g. vasodilators, tricyclic antidepressants, alcohol), the
blood pressure lowering effect may be increased.
Dapoxetine should be prescribed with caution in patients taking nicorandil due to possible
reduced orthostatic tolerance.
Gastrointestinal perforations in the context of concomitant use of nicorandil and
corticosteroids have been reported. Caution is advised when concomitant use is considered.
In patients concomitantly receiving NSAIDs including acetylsalicylic acid for both
cardiovascular prevention and anti-inflammatory doses, there is an increased risk for severe
complications such as gastrointestinal ulceration, perforation and haemorrhage (see section
4.4).
Caution is advised when nicorandil is used in combination with other medical products that
may increase potassium levels (see sections 4.4 and 4.8).
The metabolism of nicorandil is not significantly affected by cimetidine (a CYP inhibitor), or
rifampicin (a CYP3A4 inducer). Nicorandil does not affect the pharmacodynamics of
acenocoumarol.

4.6

Fertility, pregnancy and lactation

Pregnancy
There are no or limited amount of data from the use of nicorandil in pregnant women. Animal
studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity
(see section 5.3).
As a precautionary measure, it is preferable to avoid the use of Ikorel during pregnancy.
Breast-feeding
Animal studies have shown that nicorandil is excreted in small amounts into the breast milk.
It is not known whether nicorandil is excreted in human milk, therefore Ikorel is not
recommended during breastfeeding.
Fertility
There are insufficient data on fertility to estimate the risk for humans (see section 5.3).

4.7

Effects on ability to drive and use machines

Ikorel has an influence on the ability to drive and use machines. Indeed, as with other
vasodilators, blood pressure lowering effects as well as dizziness and feeling weakness
induced by nicorandil can reduce the ability to drive or to use machines. This effect can be
increased in conjunction with alcohol or other products with blood pressure lowering effect
(e.g. vasodilators, tricyclic antidepressants) (see section 4.5). Therefore, patients should be
advised not to drive or use machines if these symptoms occur.

4.8

Undesirable effects

Summary of safety profile

The most common adverse reaction reported in clinical trials is headache occurring in more
than 30% of patients, particularly in the first days of treatment and responsible for most of
study withdrawal.
Progressive dose titration may reduce the frequency of these headaches (see section 4.2).
In addition, serious adverse reactions including ulcerations and their complications (see
section 4.4) were reported during the post marketing surveillance of nicorandil.
Tabulated list of adverse reactions
The frequencies of adverse reactions reported with nicorandil are summarised in the following
table by system organ class (in MedDRA) and by frequency. Frequencies are defined as: Very
common (≥ 1/10); Common (≥ 1/100, < 1/10); Uncommon (≥ 1/1,000, < 1/100); Rare (≥
1/10,000, < 1/1,000); Very rare (< 1/10,000); Not known (cannot be estimated from the
available data).
Within each frequency grouping, adverse reactions are presented in order of decreasing
seriousness.
Very
common
Metabolism
and nutrition
disorders
Nervous system
disorders
Eye disorders

Musculoskeletal
and connective
tissue disorders
General
disorders and
administration
site conditions

Feeling of
weakness

Description of selected adverse reactions
Gastrointestinal ulcerations
Complications of gastrointestinal ulceration such as perforation, fistula, or abcess formation
sometimes leading to gastrointestinal haemorrhage and weight loss have been reported (see
section 4.4).
Additional Information
In addition, the following adverse reactions have been reported with different frequencies in
the IONA (Impact of Nicorandil in Angina) study, where nicorandil has been used on top of
standard therapy in patients with stable angina and at high risk of cardiovascular events (see
section 5.1).

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Healthcare professionals are asked to report any suspected adverse reactions via the Yellow
Card Scheme at www.mhra.gov.uk/yellowcard.

4.9

Overdose

Symptoms
In case of acute overdose, the likely symptomatology may be peripheral vasodilation with a
fall in blood pressure and reflex tachycardia.

Management
Monitoring cardiac function and general supportive measures are recommended. If not
successful, increase in circulating plasma volume by fluid substitution is recommended. In
life-threatening situations, administration of vasopressors must be considered.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Other vasodilators used in cardiac disease, ATC code:
C01DX16
Mechanism of action
Nicorandil, a nicotinamide ester, is a vasodilator agent with a dual mechanism of action,
which leads to relaxtion of smooth tonic vascular muscles in both venous and arterial part of
vessels.
It possesses a potassium channel opening effect. This activation of potassium channels
induces vascular cell membrane hyperpolarisation with an arterial muscle relaxant effect,
thereby leading to arterial dilation and afterload reduction. In addition, the activation of the
potassium channel leads to cardioprotective effects mimicking ischemic preconditioning.
Due to its nitrate moiety, nicorandil also relaxes vascular smooth muscle, particularly in the
venous system via an increase in intracellular cyclic guanosine monophosphate (cGMP). This
results in an increased pooling in capacitance vessels with a decrease in preload.
Pharmacodynamic effects
Nicorandil has been shown to exert a direct effect on coronary arteries, both on normal and
stenotic segments, without leading to a steal phenomenon. Furthermore, the reduction of enddiastolic pressure and wall tension decreases the extravascular component of vascular
resistance. Ultimately, this results in an improved oxygen balance in the myocardium and
improved blood flow in the post-stenotic areas of the myocardium.
Furthermore, nicorandil has demonstrated a spasmolytic activity in both in vitro and in vivo
studies and reverses coronary spasm induced by methacholine or noradrenalin.
Nicorandil has no direct effect on myocardial contractility.
Clinical efficacy and safety
The IONA study was a randomised, double blind, placebo controlled study carried out in
5126 patients more than 45 years old with chronic stable angina, treated with standard antianginal therapies and at high risk of cardiovascular events defined by either: 1) previous
myocardial infarction, or 2) coronary artery bypass grafting , or 3) coronary artery disease
confirmed by angiography, or a positive exercise test in the previous two years, together with
one of the following: left ventricular hypertrophy on the ECG, left ventricular ejection
fraction ≤ 45%, or an end diastolic dimension of > 55 mm, age ≥ 65, diabetes, hypertension,
peripheral vascular disease, or cerebrovascular disease. Patients were excluded from the
study if they were receiving a sulphonylurea as it was felt these patients may not benefit;
(sulphonylurea agents have the potential to close potassium channels and may thus antagonise
some of the effects of nicorandil). Study follow up for endpoint analysis was between 12 and
36 months with a mean of 1.6 years.

Nicorandil pharmacokinetics are linear from 5 mg to 40 mg.
Absorption
After oral administration, nicorandil is absorbed rapidly and completely from the
gastrointestinal tract, independent from food intake. The absolute bioavailability is about
75%. There is no significant hepatic first pass effect. Maximum plasma concentrations (Cmax)
are reached after about 30 to 60 minutes. The plasma concentration (and the area under the
curve (AUC)) shows a linear proportionality to the dose.
Steady state is rapidly achieved (within 4 to 5 days) during repeated oral administration (bid
regimen). At steady state, the accumulation ration (based on AUC) is around 2 for 20 mg bid
tablet and 1.7 for 10 mg bid tablet.
Distribution
Distribution of the product throughout the body remains stable, irrespective of dose, within
the therapeutic range.
The volume of distribution of nicorandil after intravenous (iv) dosing is 1.04 L/kg of body
weight. Nicorandil is only slightly bound to human plasma proteins (bound fraction estimated
at about 25%).
Biotransformation
Nicorandil is principally metabolised in the liver by denitration into a series of compounds
without cardiovascular activity. In plasma unchanged nicorandil accounted for 45.5% of the
radioactive AUC and the alcohol metabolite, N-(20hydroxyethyl)-nicotinamide for 40.5%.
The other metabolites accounted for the remaining 20% of the radioactive AUC.
Nicorandil is mainly eliminated in urine as metabolites since parent product is less than 1% of
the administered dose in human urine (0 – 48 hours). N-(2-hydroxyethyl)-nicotinamide is the
most abundant metabolite (about 8.9% of the administered dose within 48 hours) followed by
nicotinuric acid (5.7%), nicotinamide (1.34%), N-methyl-nicotinamide (0.61%) and nicotinic
acid (0.40%). These metabolites represent the major route of transformation of nicorandil.
Elimination
Decrease in plasma concentrations occurs in two phases:
• a rapid phase with a half-life of 1 hour approximately, representing 96% of the plasma
exposure;
• a slow elimination phase occurring approximately 12 hours following 20 mg oral dose bid.
After 4-5mg intravenous dosing (5 min infusion), the total body clearance was approximately
40-55 L/hour.
Nicorandil and its metabolites are mainly excreted by urinary route, faecal excretion being
very low.
Special patient groups
No clinically relevant modifications of the nicorandil pharmacokinetic profile is evidenced in
population at risk such as elderly people, liver disease patients and chronic renal failure
patients.

Pharmacokinetic interactions
The metabolism of nicorandil appears not to be significantly modified by cimetidine or
rifampicin, respectively an inhibitor and an inducer of liver microsomal mixed-function
oxidases.

5.3

Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.
Impairment of fertility
Fertility studies showed no effects on mating ability in either male or female rats, decreases in
the number of live foetuses and implantation sites were noted at high doses. Histopathological
changes of the testes (diminished spermatogenic cells) were determined in repeated dose
toxicity studies. Additonal investigative studies for testicular toxicity revealed decreased
blood flow in the testis and decreased blood levels of testosterone. These results suggest that
testicular toxicity by nicorandil is related to a sustained decrease in blood flow caused by
reduction of cardiac output. Upon cessation of treatment, recovery from nicorandil-induced
testicular toxicity was observed after 4 weeks; which indicates that the observed changes are
reversible.
Embryotoxicity and peri- and post-natal toxicity
Radioactivity passed through the placenta in pregnant rats after administration of
radioactively marked nicorandil.
Following exposure to nicorandil at doses that were maternally toxic, embryotoxicity was
observed in the rat and rabbit. There was no evidence of teratogenicity (rat and rabbit), or
abnormal pre- or post-natal physical or behavioural development (rat).

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